Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

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• 作者：María-José Ariza (1)
  Miguel-ángel Sánchez-Chaparro (1) (2) (3)
  Francisco-Javier Barón (4)
  Ana-María Hornos (2)
  Eva Calvo-Bonacho (2)
  José Rioja (1)
  Pedro Valdivielso (1) (3)
  José-Antonio Gelpi (2)
  Pedro González-Santos (1) (3)
  
• 刊名：BMC Medical Genetics
• 出版年：2010
• 出版时间：December 2010
• 年：2010
• 卷：11
• 期：1
• 全文大小：680KB
• 参考文献：1. Visvikis-Siest S, Marteau JB: Genetic variants predisposing to cardiovascular disease. / Curr Opin Lipidol 2006, 17 (2) : 139-1. CrossRef
  2. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, Boekholdt SM, Khaw KT, Gudnason V: Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. / Circulation 2007, 115 (4) : 450-58. CrossRef
  3. Valdivielso P, Sanchez-Chaparro MA, Calvo-Bonacho E, Cabrera-Sierra M, Sainz-Gutierrez JC, Fernandez-Labandera C, Fernandez-Meseguer A, Quevedo-Aguado L, Moraga MR, Galvez-Moraleda A, Gonzalez-Quintela A, Roman-Garcia J, ICARIA (Ibermutuamur CArdiovascular RIsk Assesment) study group: Association of moderate and severe hypertriglyceridemia with obesity, diabetes mellitus and vascular disease in the Spanish working population: results of the ICARIA study. / Atherosclerosis 2009, 207 (2) : 573-78. CrossRef
  4. Morrison AC, Bare LA, Chambless LE, Ellis SG, Malloy M, Kane JP, Pankow JS, Devlin JJ, Willerson JT, Boerwinkle E: Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. / Am J Epidemiol 2007, 166 (1) : 28-5. CrossRef
  5. Merkel M, Eckel RH, Goldberg IJ: Lipoprotein lipase: genetics, lipid uptake, and regulation. / J Lipid Res 2002, 43 (12) : 1997-006. CrossRef
  6. Pennacchio LA, Olivier M, Hubacek JA, Cohen JC, Cox DR, Fruchart JC, Krauss RM, Rubin EM: An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. / Science 2001, 294 (5540) : 169-3. CrossRef
  7. Merkel M, Heeren J: Give me A5 for lipoprotein hydrolysis! / J Clin Invest 2005, 115 (10) : 2694-. CrossRef
  8. Jakel H, Nowak M, Helleboid-Chapman A, Fruchart-Najib J, Fruchart JC: Is apolipoprotein A5 a novel regulator of triglyceride-rich lipoproteins? / Ann Med 2006, 38 (1) : 2-0. CrossRef
  9. Mahley RW, C RS Jr: Apolipoprotein E: far more than a lipid transport protein. / Annu Rev Genomics Hum Genet 2000, 1: 507-7. CrossRef
  10. Hara M, Iso ON, Satoh H, Noto H, Togo M, Ishibashi S, Kimura S, Kadowaki T, Hashimoto Y, Tsukamoto K: Differential effects of apolipoprotein E isoforms on lipolysis of very low-density lipoprotein triglycerides. / Metabolism 2006, 55 (8) : 1129-4. CrossRef
  11. Hu Y, Liu W, Huang R, Zhang X: A systematic review and meta-analysis of the relationship between lipoprotein lipase Asn291Ser variant and diseases. / J Lipid Res 2006, 47 (9) : 1908-4. CrossRef
  12. Wittrup HH, Andersen RV, Tybjaerg-Hansen A, Jensen GB, Nordestgaard BG: Combined analysis of six lipoprotein lipase genetic variants on triglycerides, high-density lipoprotein, and ischemic heart disease: cross-sectional, prospective, and case-control studies from the Copenhagen City Heart Study. / J Clin Endocrinol Metab 2006, 91 (4) : 1438-5. CrossRef
  13. Chen Q, Razzaghi H, Demirci FY, Kamboh MI: Functional significance of lipoprotein lipase HindIII polymorphism associated with the risk of coronary artery disease. / Atherosclerosis 2008, 200 (1) : 102-. CrossRef
  14. Corella D, Guillen M, Saiz C, Portoles O, Sabater A, Folch J, Ordovas JM: Associations of LPL and APOC3 gene polymorphisms on plasma lipids in a Mediterranean population: interaction with tobacco smoking and the APOE locus. / J Lipid Res 2002, 43 (3) : 416-7.
  15. Rip J, Nierman MC, Ross CJ, Jukema JW, Hayden MR, Kastelein JJ, Stroes ES, Kuivenhoven JA: Lipoprotein lipase S447X: a naturally occurring gain-of-function mutation. / Arterioscler Thromb Vasc Biol 2006, 26 (6) : 1236-5. CrossRef
  16. Tang W, Apostol G, Schreiner PJ, Jacobs DR Jr, Boerwinkle E, Fornage M: Associations of Lipoprotein Lipase Gene Polymorphisms with Longitudinal Plasma Lipid Trends in Young Adults: the CARDIA Study. / Circ Cardiovasc Genet 2010, in press.
  17. Pennacchio LA, Olivier M, Hubacek JA, Krauss RM, Rubin EM, Cohen JC: Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels. / Hum Mol Genet 2002, 11 (24) : 3031-. CrossRef
  18. Hubacek JA: Apolipoprotein A5 and triglyceridemia. Focus on the effects of the common variants. / Clin Chem Lab Med 2005, 43 (9) : 897-02. CrossRef
  19. Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, Keavney B, Collins R, Wiman B, de Faire U, Danesh J: Association of apolipoprotein E genotypes with lipid levels and coronary risk. / Jama 2007, 298 (11) : 1300-1. CrossRef
  20. Polychronakos C: Common and rare alleles as causes of complex phenotypes. / Curr Atheroscler Rep 2008, 10 (3) : 194-00. CrossRef
  21. Sanchez-Chaparro MA, Roman-Garcia J, Calvo-Bonacho E, Gomez-Larios T, Fernandez-Meseguer A, Sainz-Gutierrez JC, Cabrera-Sierra M, Garcia-Garcia A, Rueda-Vicente J, Galvez-Moraleda A, Gonzalez-Quintela A: [Prevalence of cardiovascular risk factors in the Spanish working population]. / Rev Esp Cardiol 2006, 59 (5) : 421-0. CrossRef
  22. Sanchez-Chaparro MA, Calvo-Bonacho E, Gonzalez-Quintela A, Fernandez-Labandera C, Cabrera M, Sainz JC, Fernandez-Meseguer A, Banegas JR, Ruilope LM, Valdivielso P, Roman-Garcia J, Ibermutuamur Cardiovascular Risk Assessment (ICARIA) Study Group: Occupation-related differences in the prevalence of metabolic syndrome. / Diabetes Care 2008, 31 (9) : 1884-885. CrossRef
  23. National Cholesterol Education Program [http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf] 2007.
  24. R Developement Core Team: R: A language and Environment for Satatistical Computing. [http://www.R-project.org] R Fondation for Satatistical Computing, Vienna, Austria; 2008.
  25. Gonzalez JR, Armengol L, Sole X, Guino E, Mercader JM, Estivill X, Moreno V: SNPassoc: an R package to perform whole genome association studies. / Bioinformatics 2007, 23 (5) : 644-45. CrossRef
  26. Talmud PJ, Stephens JW: Lipoprotein lipase gene variants and the effect of environmental factors on cardiovascular disease risk. / Diabetes Obes Metab 2004, 6 (1) : 1-. CrossRef
  27. Wittrup HH, Tybjaerg-Hansen A, Nordestgaard BG: Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis. / Circulation 1999, 99 (22) : 2901-.
  28. Choumerianou DM, Maumus S, Skoumas J, Pitsavos C, Stefanadis C, Visvikis-Siest S, Dedoussis GV: Polymorphisms associated with apolipoprotein B levels in Greek patients with familial hypercholesterolemia. / Clin Chem Lab Med 2006, 44 (7) : 799-06. CrossRef
  29. Chandak GR, Ward KJ, Yajnik CS, Pandit AN, Bavdekar A, Joglekar CV, Fall CH, Mohankrishna P, Wilkin TJ, Metcalf BS, Weedon MN, Frayling TM, Hattersley AT: Triglyceride associated polymorphisms of the APOA5 gene have very different allele frequencies in Pune, India compared to Europeans. / BMC Med Genet 2006, 7: 76. CrossRef
  30. Perez-Martinez P, Corella D, Shen J, Arnett DK, Yiannakouris N, Tai ES, Orho-Melander M, Tucker KL, Tsai M, Straka RJ, Province M, Kai CS, Perez-Jimenez F, Lai CQ, Lopez-Miranda J, Guillen M, Parnell LD, Borecki I, Kathiresan S, Ordovas JM: Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states. / Am J Clin Nutr 2009, 89 (1) : 391-99. CrossRef
  31. Corella D, Guillen M, Saiz C, Portoles O, Sabater A, Cortina S, Folch J, Gonzalez JI, Ordovas JM: Environmental factors modulate the effect of the APOE genetic polymorphism on plasma lipid concentrations: ecogenetic studies in a Mediterranean Spanish population. / Metabolism 2001, 50 (8) : 936-4. CrossRef
  32. Humphries SE, Nicaud V, Margalef J, Tiret L, Talmud PJ: Lipoprotein lipase gene variation is associated with a paternal history of premature coronary artery disease and fasting and postprandial plasma triglycerides: the European Atherosclerosis Research Study (EARS). / Arterioscler Thromb Vasc Biol 1998, 18 (4) : 526-4.
  33. Haddy N, De Bacquer D, Chemaly MM, Maurice M, Ehnholm C, Evans A, Sans S, Do Carmo Martins M, De Backer G, Siest G, Visvikis S: The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe. / Eur J Hum Genet 2002, 10 (12) : 841-0. CrossRef
  34. Frikke-Schmidt R, Sing CF, Nordestgaard BG, Steffensen R, Tybjaerg-Hansen A: Subsets of SNPs define rare genotype classes that predict ischemic heart disease. / Hum Genet 2007, 120 (6) : 865-77. CrossRef
  35. Hubacek JA, Lanska V, Skodova Z, Adamkova V, Poledne R: Sex-specific interaction between APOE and APOA5 variants and determination of plasma lipid levels. / Eur J Hum Genet 2008, 16 (1) : 135-38. CrossRef
  36. Hubacek JA, Horinek A, Skodova Z, Adamkova V, Ceska R, Zlatohlavek L, Vrablik M: Hypertriglyceridemia: interaction between APOE and APOAV variants. / Clin Chem 2005, 51 (7) : 1311-. CrossRef
  37. Sousa MO, Alia P, Pinto X, Corbella E, Navarro MA: Interaction between APOA5 -1131T>C and APOE polymorphisms and their association with severe hypertriglyceridemia. / Clin Chim Acta 2008, 395 (1-) : 68-1. CrossRef
  38. Brisson D, St-Pierre J, Santure M, Hudson TJ, Despres JP, Vohl MC, Gaudet D: Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects. / Int J Obes (Lond) 2007, 31 (8) : 1325-333. CrossRef
  39. Pitsavos C, Choumerianou DM, Skoumas J, Maumus S, Stefanadis C, Dedoussis GV, Visvikis-Siest S: Apolipoprotein E polymorphism is not associated with lipid levels and coronary artery disease in Greek patients with familial hypercholesterolaemia. / Clin Exp Med 2005, 5 (4) : 196-01. CrossRef
  40. Wang J, Ban MR, Zou GY, Cao H, Lin T, Kennedy BA, Anand S, Yusuf S, Huff MW, Pollex RL, Hegele RA: Polygenic determinants of severe hypertriglyceridemia. / Hum Mol Genet 2008, 17 (18) : 2891-899. CrossRef
  41. Ordovas JM, Tai ES: Why study gene-environment interactions? / Curr Opin Lipidol 2008, 19 (2) : 158-7. CrossRef
  42. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/11/66/prepub
  
• 作者单位：María-José Ariza (1)
  Miguel-ángel Sánchez-Chaparro (1) (2) (3)
  Francisco-Javier Barón (4)
  Ana-María Hornos (2)
  Eva Calvo-Bonacho (2)
  José Rioja (1)
  Pedro Valdivielso (1) (3)
  José-Antonio Gelpi (2)
  Pedro González-Santos (1) (3)
  
  1. Departamento de Medicina y Dermatología, Facultad de Medicina, Laboratorio de Lípidos y Arteriosclerosis, Centro de Investigaciones Médico-Sanitarias (CIMES), Universidad de Málaga, Campus de Teatinos, 29010, Málaga, Spain
  2. Ibermutuamur Cardiovascular Risk Assessment (ICARIA) Study Group, Ibermutuamur: Mutua de Accidentes de Trabajo y Enfermedades Profesionales de la Seguridad Social n° 274, 28043, Madrid, Spain
  3. Departamento of Medicina Interna, Hospital Universitario Virgen de la Victoria, Campus de Teatinos, 29010, Málaga, Spain
  4. Departamento de Bioestadística, Facultad de Medicina, Universidad de Málaga, Campus de Teatinos, 29010, Málaga, Spain
  
• ISSN：1471-2350

文摘

Background Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information. Methods A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL -HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5 -S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG ?1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption. Results We found a significant lowering effect of the LPL -HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE -ε4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; p < 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; p < 0.001) were associated with HTG. Conclusion Our results showed a significant independent additive effect on TG levels of the LPL polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of APOA5, and the ε4 allele of APOE in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia.